HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 4, 2505-2511, January 26, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/4/2505    most recent M609603200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liu, Y. Articles by Rosenblum, J. S. Search for Related Content PubMed PubMed Citation Articles by Liu, Y. Articles by Rosenblum, J. S. Social Bookmarking                      What's this?

Polo-like Kinases Inhibited by Wortmannin

LABELING SITE AND DOWNSTREAM EFFECTS^*

Yongsheng Liu¹, Ning Jiang¹, Jiangyue Wu, Wei Dai^¶2, and Jonathan S. Rosenblum³

From the ActivX Biosciences, Inc., La Jolla, California 92037, the Department of Medicine, New York Medical College, Valhalla, New York 10595, and the ^¶Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987

Polo-like kinases play crucial roles throughout mitosis. We previously reported that wortmannin potently inhibits Polo-like kinase 1 (Plk1). In this study, we show that wortmannin also strongly inhibits Polo-like kinase 3 (Plk3). To further characterize this inhibition, we identified the sites of labeling on Plk1 and Plk3 targeted by AX7503, a tetramethylrhodamine-wortmannin conjugate. AX7503 labeling on Plk1 and Plk3 was found to occur on a conserved ATP binding site residue. In addition, we show that wortmannin inhibits Plk3 activity in live cells at concentrations commonly used to inhibit the more well known targets of wortmannin, the phosphoinositide 3-kinases. Importantly, we found that inhibition of Plk3 by wortmannin lead to a decrease in phosphorylation of p53 on serine 20 induced by DNA damage, demonstrating the effect of wortmannin on a downstream Plk3 target. Taken together, our results suggest that wortmannin can affect multiple functions of Plk3 in cell cycle progression and at the DNA damage check point. The identification of the labeling sites of Plk1 and Plk3 by AX7503 may be useful in designing more effective compounds to target Polo-like kinases for cancer treatment and also may be useful for the structural study of Plk domains.

Received for publication, October 11, 2006 , and in revised form, November 28, 2006.

^* This work was supported by National Institutes of Health Grants 5R44-CA097462 (to J. S. R.) and RO1-CA74229 (to W. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 845-731-3555; Fax: 845-731-3611; E-mail: wei.dai{at}med.nyu.edu. ³ To whom correspondence may be addressed: 11025 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-526-2511; Fax: 858-558-5565; E-mail: jonr{at}activx.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?